The drug abuse problem in general and the wide spread use of marijuana in particular has focused attention on the chemistry and pharmacology of cannabinoids. Although rapid advances have been made in the chemistry and pharmacology of this class of compounds, the mechanisms involved in producing the various central nervous effects (CNS) have not been established. The long term goal of the synthetic program is to develop A9-tetrahydrocannabinol (THC) analogs which will prove to be useful tools in elucidating the mechanism of action of cannabinoids. The present emphasis will be directed towards: (a) development of CB1 selective agonists (b) development of allosteric modulators of the cannabinoid CB1 receptors (c) studying peripheral acting agonists and antagonists (d) elucidation of ligand-CB1 receptor iterations (e) development of CB1 neutral antagonist/inverse agonists which are structurally related to THC and (f) generation of new biological leads. All these goals represent a continuation of the current program which has generated several noteworthy leads. The specific aims are (1) development of CB1 selective agonists, (2) development of allosteric modulators of the CB1 receptors, (3) examining peripheral acting agonists and antagonists, (4) elucidation of ligand-CB1 receptor interactions, (5) development of CB1 neutral/inverse agonists which are structurally related to THC, and (6) generate new biological leads. The knowledge gained from the synthesis and pharmacological study of these analogs could be vital in the study of Structure Activity Relationships(SAR), tolerance, dependence and in the development of therapeutically useful drugs, and will lead to a better understanding of the mechanism of action of cannabinoids and will help combat the problem of drug abuse.